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Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis.

Weis S, Cui J, Barnes L, Cheresh D - J. Cell Biol. (2004)

Bottom Line: VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function.We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes.Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

ABSTRACT
VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function. Therefore, we considered whether this property of VEGF might contribute to tumor cell extravasation and metastasis. To test this, mice lacking the Src family kinases Src or Yes, which maintain endothelial barrier function in the presence of VEGF, were injected intravenously with VEGF-expressing tumor cells. We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes. At the molecular level, VEGF compromises the endothelial barrier by disrupting a VE-cadherin-beta-catenin complex in lung endothelium from wild-type, but not Yes-deficient, mice. Disrupting the endothelial barrier directly with anti-VE-cadherin both amplifies metastasis in normal mice and overcomes the genetic resistance in Yes-deficient mice. Pharmacological blockade of VEGF, VEGFR-2, or Src stabilizes endothelial barrier function and suppresses tumor cell extravasation in vivo. Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.

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Tumor cell accumulation hours-to-days after tumor cell injection. To determine a time line for CT26 tumor cell extravasation after i.v. inoculation, we prepared lungs for analysis by transmission EM. By 1–3 h, tumor cells (T) had extended protrusions toward endothelial cells (EC) (A) or extended processes between EC junctions to contact the underlying basal lamina (BL) (B). (C) At 3 h, we observed individual extravasated tumor cells immediately outside the blood vessels where they were typically lodged in the extracellular space between an EC and a pneumocyte (PC). (D) This ultimately gave way to metastatic foci containing numerous tumor cells by day 4. Bars: (A–C) 1 μm; (D) 5 μm.
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fig1: Tumor cell accumulation hours-to-days after tumor cell injection. To determine a time line for CT26 tumor cell extravasation after i.v. inoculation, we prepared lungs for analysis by transmission EM. By 1–3 h, tumor cells (T) had extended protrusions toward endothelial cells (EC) (A) or extended processes between EC junctions to contact the underlying basal lamina (BL) (B). (C) At 3 h, we observed individual extravasated tumor cells immediately outside the blood vessels where they were typically lodged in the extracellular space between an EC and a pneumocyte (PC). (D) This ultimately gave way to metastatic foci containing numerous tumor cells by day 4. Bars: (A–C) 1 μm; (D) 5 μm.

Mentions: To study the extravasation phase of metastasis, we injected VEGF-expressing CT26 murine colon carcinoma cells i.v. into mice and evaluated the lungs from these animals at the ultrastructural level after hours to days. In normal mice 1–3 h after inoculation, CT26 cells can be observed extending processes between gaps in the endothelium (Fig. 1, A and B), suggesting that a breach in endothelial barrier function may facilitate extravasation. In fact, single cells extravasate within hours of entering the circulation (Fig. 1 C), and form multicellular lesions after several days (Fig. 1 D). These studies suggest the possibility that VEGF, which induces such endothelial gaps (Weis et al., 2004), may facilitate tumor cell extravasation.


Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis.

Weis S, Cui J, Barnes L, Cheresh D - J. Cell Biol. (2004)

Tumor cell accumulation hours-to-days after tumor cell injection. To determine a time line for CT26 tumor cell extravasation after i.v. inoculation, we prepared lungs for analysis by transmission EM. By 1–3 h, tumor cells (T) had extended protrusions toward endothelial cells (EC) (A) or extended processes between EC junctions to contact the underlying basal lamina (BL) (B). (C) At 3 h, we observed individual extravasated tumor cells immediately outside the blood vessels where they were typically lodged in the extracellular space between an EC and a pneumocyte (PC). (D) This ultimately gave way to metastatic foci containing numerous tumor cells by day 4. Bars: (A–C) 1 μm; (D) 5 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172541&req=5

fig1: Tumor cell accumulation hours-to-days after tumor cell injection. To determine a time line for CT26 tumor cell extravasation after i.v. inoculation, we prepared lungs for analysis by transmission EM. By 1–3 h, tumor cells (T) had extended protrusions toward endothelial cells (EC) (A) or extended processes between EC junctions to contact the underlying basal lamina (BL) (B). (C) At 3 h, we observed individual extravasated tumor cells immediately outside the blood vessels where they were typically lodged in the extracellular space between an EC and a pneumocyte (PC). (D) This ultimately gave way to metastatic foci containing numerous tumor cells by day 4. Bars: (A–C) 1 μm; (D) 5 μm.
Mentions: To study the extravasation phase of metastasis, we injected VEGF-expressing CT26 murine colon carcinoma cells i.v. into mice and evaluated the lungs from these animals at the ultrastructural level after hours to days. In normal mice 1–3 h after inoculation, CT26 cells can be observed extending processes between gaps in the endothelium (Fig. 1, A and B), suggesting that a breach in endothelial barrier function may facilitate extravasation. In fact, single cells extravasate within hours of entering the circulation (Fig. 1 C), and form multicellular lesions after several days (Fig. 1 D). These studies suggest the possibility that VEGF, which induces such endothelial gaps (Weis et al., 2004), may facilitate tumor cell extravasation.

Bottom Line: VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function.We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes.Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

ABSTRACT
VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function. Therefore, we considered whether this property of VEGF might contribute to tumor cell extravasation and metastasis. To test this, mice lacking the Src family kinases Src or Yes, which maintain endothelial barrier function in the presence of VEGF, were injected intravenously with VEGF-expressing tumor cells. We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes. At the molecular level, VEGF compromises the endothelial barrier by disrupting a VE-cadherin-beta-catenin complex in lung endothelium from wild-type, but not Yes-deficient, mice. Disrupting the endothelial barrier directly with anti-VE-cadherin both amplifies metastasis in normal mice and overcomes the genetic resistance in Yes-deficient mice. Pharmacological blockade of VEGF, VEGFR-2, or Src stabilizes endothelial barrier function and suppresses tumor cell extravasation in vivo. Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.

Show MeSH
Related in: MedlinePlus